EP4129335A1 - Conjugué médicament-anticorps anti c-met et ses applications - Google Patents

Conjugué médicament-anticorps anti c-met et ses applications Download PDF

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EP4129335A1
EP4129335A1 EP21863586.0A EP21863586A EP4129335A1 EP 4129335 A1 EP4129335 A1 EP 4129335A1 EP 21863586 A EP21863586 A EP 21863586A EP 4129335 A1 EP4129335 A1 EP 4129335A1
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Prior art keywords
antibody
antigen
drug conjugate
binding fragment
group
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German (de)
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EP4129335A4 (fr
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Jianmin Fang
Changjiang Huang
Xuejing YAO
Wenting LUO
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Remegen Co Ltd
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Remegen Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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    • A61K47/6857—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from lung cancer cell
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6875—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody being a hybrid immunoglobulin
    • A61K47/6877—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody being a hybrid immunoglobulin the antibody being an immunoglobulin containing regions, domains or residues from different species
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the present disclosure relates to the field of antibody-drug conjugates, and specifically relates to an antibody-drug conjugate targeting c-Met and applications thereof.
  • c-Met (tyrosine-protein kinase Met) is a proto-oncogene (Reference 1: Edakuni G, Sasatomi E, Satoh T, et al. Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma. [J]. Pathology International, 2010, 51(3):172-178 ), and the post-transcriptional product is hepatocyte growth factor (HGF) receptor. Consistent with HGF, its precursor is a single chain, which is broken into ⁇ chain and ⁇ chain connected by disulfide bonds after various modifications. Cellularly, c-Met is mainly divided into intracellular and extracellular parts.
  • the extracellular region includes SD (Sema domain), PSID (plexin-semaphorin-integrin domain) and IPTD (immunoglobulin-like regions in plexins and transcription factors domain), and the intracellular region mainly includes JD (juxtamembrane domain) and TKCD (a tyrosine kinase domain (TK domain) and a c-terminal docking site) (Reference 2: Sattler M, Reddy M M, Hasina R, et al. The role of the c-Met pathway in lung cancer and the potential for targeted therapy [J]. Therapeutic Advances in Medical Oncology, 2011, 3(4):171-84 .).
  • c-Met is the receptor of HGF.
  • Ras-Rac signaling pathway leads to the movement of the cytoskeleton; (2) Ras-MAPK cascade promotes cell division and differentiation; (3) PI3K-FAK signaling pathway promotes cell migration and invasion; and (4) PI3K-AKT signaling pathway promotes cell survival.
  • the HGF/c-Met signaling pathway promotes growth and migration of tumor cells.
  • c-Met is overexpressed on many tumor cells, mainly head and neck squamous carcinoma and hypopharyngeal carcinoma, but also on renal cell carcinoma, colorectal cancer, lung adenocarcinoma, ovarian cancer, liver cancer, breast cancer, bladder cancer, non-small cell carcinoma and gastric cancer.
  • the high expression in tumor cells and low expression in normal cells of c-Met makes c-Met an excellent target for targeted therapy.
  • Antibody-drug conjugate is a biological drug that links a biologically active drug and an antibody through a chemical linker.
  • ADC Antibody-drug conjugate
  • the biological drugs targeting c-Met in the research or clinical stage are mainly monoclonal antibodies, and there are few antibody-drug conjugates (ADC) (Reference 4: LILIANE GOETSCH, A. J. Anti-CMET antibody and its use for the detection and the diagnosis of cancer. WO2011020925 A1, 2012 ).
  • ADC antibody-drug conjugates
  • SHR-A1403 for injection developed by Hengrui Medicine is an ADC formed by chemical coupling of a humanized anti-c-Met monoclonal antibody and a microtubule inhibitor.
  • this antibody-drug conjugate By binding to c-Met on the surface of tumor cells, this antibody-drug conjugate can be endocytosed into tumor cells, and then release small molecule toxins after degradation in lysosome, which plays a role in killing tumor cells (Reference 5: Ki-Hyun Kim Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy, Experimental & Molecular Medicine (2017) 49, e307 ).
  • ABBVie's ABBV-399 is also in phase I clinical research in the United States. It is a conjugate of ABT-700 antibody and MMAE with a DAR (drug-to-antibody ratio) of 3.1 for the treatment of c-Met-overexpressing non-small cell lung cancer.
  • DAR drug-to-antibody ratio
  • the results of early clinical trials of c-Met showed that ABBV-399 can produce cytotoxic effect on c-Met positive cancer cells.
  • the phase I clinical trial (NCT02099058) was conducted in 29 patients with c-Met-positive NSCLC, and the safety and efficacy of ABBV-399 alone or in combination with erlotinib were preliminarily investigated.
  • ADC drugs can effectively combine these well-targeted monoclonal antibodies and cytotoxins to maintain targeting while enhancing the killing effect on cells.
  • ADCs targeting c-Met is relatively slow, few in the clinical stage, and they are in the early clinical stage, such as ABBVie's ABBV-399 and Hengrui Medicine's SHR-A1403, both of which are in phase I clinical trials.
  • the safety of drugs and effective targeted indications are still under exploration. Therefore, there is an urgent need to develop anti-c-Met antibody-drug conjugates with better efficacy and safety in clinical practice, so that more targeted indications can be expanded for effective treatment.
  • the present disclosure provides an antibody targeting c-Met or antigen-binding fragment thereof and use thereof in the treatment of cancer.
  • the present disclosure also provides an antibody-drug conjugate (ADC) comprising the above-mentioned antibody, a nucleotide encoding the above-mentioned c-Met antibody, a polynucleotide combination, an expression vector and a host cell, a pharmaceutical composition comprising the above-mentioned antibody targeting c-Met or antibody-drug conjugate, as well as their use in the manufacture of a medicament for the treatment or prevention of a cancer.
  • ADC antibody-drug conjugate
  • the present disclosure provides a humanized antibody targeting c-Met or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
  • the humanized antibody or antigen-binding fragment thereof is selected from the group consisting of monoclonal antibody, bispecific antibody, multispecific antibody, recombinant protein comprising the antigen-binding fragment, Fab fragment, F(ab') fragment, F(ab') 2 fragment, Fv fragment, dAb, Fd, and single chain antibody (scFv).
  • the antibody or antigen-binding fragment further comprises a constant region of an immunoglobulin, wherein the immunoglobulin is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
  • the heavy chain variable region of the antibody or antigen-binding fragment thereof has an amino acid sequence shown in SEQ ID NO: 7; and/or the light chain variable region of the antibody or antigen-binding fragment thereof has an amino acid sequence shown in SEQ ID NO: 8.
  • amino acid sequence shown in SEQ ID NO: 7 is as follows:
  • amino acid sequence shown in SEQ ID NO: 8 is as follows:
  • the heavy chain variable region of the antibody or antigen-binding fragment thereof has an amino acid sequence shown in SEQ ID NO: 9; and/or the light chain variable region of the antibody or antigen-binding fragment thereof has an amino acid sequence shown in SEQ ID NO: 10.
  • amino acid sequence shown in SEQ ID NO: 9 is as follows:
  • amino acid sequence shown in SEQ ID NO: 10 is as follows:
  • the present disclosure also relates to an isolated polynucleotide encoding the antibody or antigen-binding fragment thereof described in any one of the above.
  • the present disclosure also relates to a nucleic acid construct comprising the above-described polynucleotide.
  • the above-described nucleic acid construct is preferably an expression vector, wherein the polynucleotide is operably linked to a regulatory sequence that permits expression of a polypeptide encoded by the polynucleotide in a host cell or cell-free expression system.
  • the present disclosure also relates to a host cell comprising the above-described polynucleotide or expression vector, and the host cell is preferably selected from the group consisting of a prokaryotic cell, eukaryotic cell, yeast cell, mammalian cell and E. coli cell; and further, the host cell is preferably selected from the group consisting of a CHO cell, NS0 cell, Sp2/0 cell and BHK cell.
  • the present disclosure also provides a method for producing the antibody or antigen-binding fragment thereof described in any one of the above, the method comprising: culturing the above-described host cell under a condition allowing the expression of the above-described nucleic acid construct, and recovering the produced expressed protein from the culture.
  • the present disclosure also provides an antibody-drug conjugate targeting c-Met, which is a conjugate of any one of the above-mentioned antibody or antigen-binding fragment thereof and one or more therapeutic agents.
  • the therapeutic agent is selected from the group consisting of a cytotoxic molecule, immunoenhancer and radioisotope
  • the cytotoxic molecule includes but is not limited to a tubulin inhibitor or DNA damaging agent; further preferably, the tubulin inhibitor includes but is not limited to a cytotoxic molecule of dolastatins and auristatins and a cytotoxic molecule of maytansines
  • the DNA damaging agent includes but is not limited to calicheamicins, duocarmycins, pyrrolobenzodiazepine derivatives (PBD), camptothecins and derivatives thereof, SN-38 and Dxd
  • the cytotoxic molecule of auristatins includes but is not limited to MMAE, MMAF, and a derivative thereof
  • the cytotoxic molecule of maytansines includes but is not limited to DM1, DM4, and a derivative thereof.
  • A-(L-U)n The preferred general structural formula of the antibody-drug conjugate provided by the present disclosure is A-(L-U)n, wherein: A represents the antibody or antigen-binding fragment thereof described in any one of the above; U is an active drug unit; L is any linking group, and is covalently linked to the antibody or antigen-binding fragment A and the active drug unit U, respectively; n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; and A is linked to 1, 2, 3, 4, 5, 6, 7 or 8 of the active drug unit U through one or more of the linking group L.
  • the linking group L is covalently linked to the amino residue or thiol residue on the antibody targeting c-Met or antigen-binding fragment A; preferably, the linking group L is covalently linked to the thiol residue on the antibody targeting c-Met or antigen-binding fragment A; more preferably, the linking group L is covalently linked to the thiol residue formed after the interchain disulfide bond on the antibody targeting c-Met or antigen-binding fragment A is opened.
  • the linking group L includes a cleavable linker and a non-cleavable linker.
  • the cleavable linker comprises a peptide unit comprising 2-20 amino acids, and preferably, the peptide unit is selected from the group consisting of -valine-citrulline- (-Val-Cit-), -glycine-glycine-phenylalanine-glycine- (-Gly-Gly-Phe-Gly-), -valine-alanine- (-Val-Ala-), -valine-lysine- (-Val-Lys-), -valine-arginine- (-Val-Arg-), -phenylalanine-citrulline- (-Phe-Cit-), -phenylalanine-lysine- (-Phe-Lys-), -phenylalanine-arginine- (-Phe-Arg-) and a combination thereof.
  • L includes a structure selected from the group consisting of:
  • the active drug unit U has a structure selected from the group consisting of:
  • the antibody-drug conjugate has a structure selected from the group consisting of: wherein, n in ADC-1 is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; or wherein, n in ADC-2 is an integer selected from 1, 2, 3 and 4; or wherein, n in ADC-3 is an integer selected from 1, 2, 3 and 4; or wherein, n in ADC-4 is an integer selected from 1 and 2; or wherein, n in ADC-5 is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; or wherein, n in ADC-6 is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; or wherein, n in ADC-7 is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof and/or antibody-drug conjugate described in any one of the above, and a pharmaceutically acceptable carrier.
  • the present disclosure also provides use of any one of the above-described antibody or antigen-binding fragment thereof, polynucleotide, nucleic acid construct, expression vector, antibody-drug conjugate or pharmaceutical composition in the manufacture of a medicament for treating or preventing a cancer.
  • the cancer is a c-Met positive cancer.
  • the c-Met positive cancer includes lung cancer and gastric cancer.
  • the present disclosure also provides a method of treating a disease, comprising administering to a patient in need thereof a therapeutically effective amount of the antibody-drug conjugate or pharmaceutical composition described in any one of the above; wherein the disease is a c-Met positive cancer, preferably lung cancer and gastric cancer.
  • the present disclosure also provides a kit comprising a container, a preparation placed in the container and an optional instruction; wherein the preparation comprises the antibody, antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition described in any one of the above.
  • the present disclosure also provides use of the antibody or antigen-binding fragment thereof, antibody-drug conjugate, polynucleotide, nucleic acid construct, expression vector, or pharmaceutical composition described in any of the above in the manufacture of a medicament for treating or preventing a cancer.
  • the cancer is a solid tumor; and the solid tumor further includes lung cancer and gastric cancer.
  • the present disclosure also provides a recombinant protein comprising the antibody or antigen-binding fragment described in any one of the above.
  • the above-mentioned recombinant protein is preferably a bispecific antibody or multispecific antibody, and the multispecific antibody is preferably trispecific antibody, tetraspecific antibody, pentaspecific antibody, etc.
  • the present disclosure also provides use of any one of the above-mentioned antibody or antigen-binding fragment in the preparation of a recombinant protein.
  • the terms “pharmaceutical composition”, “combined drug”, or “pharmaceutical combination” are used interchangeably, and means a combination of at least one drug and optionally a pharmaceutically acceptable carrier or adjuvant material combined together to achieve a particular purpose.
  • the pharmaceutical composition comprises a combination that is separated in time and/or space as long as it can work together to achieve the object of the present disclosure.
  • the components contained in the pharmaceutical composition for example, the antibody, nucleic acid molecule, nucleic acid molecule combination, and/or antibody-drug conjugate according to the present disclosure
  • the ingredients contained in the pharmaceutical composition are separately administered to a subject, the ingredients can be administered to the subject simultaneously or sequentially.
  • the pharmaceutically acceptable carrier is water, a buffered aqueous solution, an isotonic saline solution such as PBS (phosphate buffer), glucose, mannitol, dextrose, lactose, starch, magnesium stearate, cellulose, magnesium carbonate, 0.3% glycerol, hyaluronic acid, ethanol or polyalkylene glycol such as polypropylene glycol, triglyceride and the like.
  • the type of the pharmaceutically acceptable carrier used depends, inter alia, on whether the composition according to the present disclosure is formulated for oral, nasal, intradermal, subcutaneous, intramuscular or intravenous administration.
  • the composition according to the present disclosure may contain a wetting agent, an emulsifier or a buffer substance as an additive.
  • compositions, vaccine or pharmaceutical formulation according to the present disclosure can be administered by any suitable route, for example, orally, nasally, intradermally, subcutaneously, intramuscularly or intravenously.
  • therapeutic agent refers to any substance or entity capable of playing a therapeutic role (e.g., treating, preventing, relieving or inhibiting any disease and/or condition), including but not limited to a chemotherapeutic agent, radiotherapy agent, immunotherapeutic agent, thermally therapeutic agent.
  • CDR region refers to the hypervariable region of the heavy and light chain of an immunoglobulin, as defined by Kabat et al. ( Kabat et al., Sequences of proteins of immunological interest, 5th Ed., U.S. Department of Health and Human Services, NIH, 1991 , and later editions). There are three heavy chain CDRs and three light chain CDRs. Depending on the circumstances, the term CDR or CDRs used herein is used to indicate one of these regions, or several or even all of these regions, which region contains most of the amino acid residues responsible for binding based on the affinity of an antibody for an antigen or its recognition epitope.
  • Consistency refers to the percentage of the same nucleotide or amino acid residues between the two sequences to be compared obtained after the optimal alignment. The percentage is purely statistical and the differences between the two sequences are randomly distributed and cover their full length. Comparisons between two nucleic acid or amino acid sequences are usually performed by comparing these sequences after aligning them in an optimal manner, and can be performed over a segment or over a "comparison window". In addition to manual implementation, the optimal alignment used for comparing sequences can also be performed by the local homology algorithm of Smith and Waterman (1981) [Ad. App. Math.
  • terapéuticaally effective amount refers to a dose sufficient to demonstrate a benefit when administered to a subject.
  • the actual amount administered, as well as the frequency and time course of administration will depend on the condition and severity of the subject to be treated. General practitioners and other doctors are ultimately responsible for the treatment prescription (for example, decision on the dose) and usually make decisions based on the disease being treated, the condition of the individual patient, the delivery site, the mode of administration, and other factors known to the doctor.
  • subject refers to a mammal, such as human, but may also refer to other animals, such as wild animals (such as heron, stork, crane), domestic animals (such as duck, goose) or experimental animals (such as orangutan, monkey, rat, mouse, rabbit, guinea pig, marmot, ground squirrel).
  • wild animals such as heron, stork, crane
  • domestic animals such as duck, goose
  • experimental animals such as orangutan, monkey, rat, mouse, rabbit, guinea pig, marmot, ground squirrel.
  • antibody includes monoclonal antibody, bispecific antibody, multispecific antibody or recombinant protein comprising antigen-binding fragment;
  • antigen-binding fragment includes Fab fragment, F(ab') fragment, F(ab') 2 fragment, Fv fragment, dAb, Fd, single chain antibody (scFv), scFv-Fc fragment or diabody, or any fragment that should be able to increase half-life by chemical modification or by incorporation into liposomes, such chemical modifications as the addition of poly(alkylene) glycols such as polyethylene glycol (“PEGylation") (PEGylated fragments known as Fv-PEG, scFv-PEG, Fab-PEG, F(ab')2-PEG or Fab'-PEG) (“PEG” refers to polyethylene glycol), and such fragment has EGFR binding activity.
  • PEGylation polyethylene glycol
  • the functional fragment will consist of or comprise partial sequences of the heavy or light variable chain of the antibody from which it is derived, which partial sequence is sufficient to retain the same binding specificity and sufficient affinity as the antibody from which it is derived, preferably for EGFR at least equal to 1/100 of the affinity of the antibody from which it is derived, more preferably at least equal to 1/10.
  • a functional fragment comprises a minimum of 5 amino acids, preferably 10, 15, 25, 50 and 100 contiguous amino acids of the antibody sequence from which it is derived.
  • humanized antibody refers to an antibody comprising a CDR region derived from a non-human antibody, and the other portion of the antibody is derived from one (or several) human antibody (antibodies). Moreover, in order to retain binding affinity, some residues of the backbone (referred to as FR) segment may be modified ( Jones et al., Nature, 321:522-525, 1986 ; Verhoeyen et al., Science, 239: 1534-1536, 1988 ; Riechmann et al., Nature, 332: 323-327, 1988 ).
  • FR backbone
  • a humanized antibody or fragment thereof according to the present disclosure can be prepared by techniques known to those skilled in the art;
  • chimeric antibody refers to an antibody in which the variable region sequence is derived from one species and the constant region sequence is derived from another species, for example, the variable region sequence is derived from a mouse antibody and the constant region sequence is derived from a human antibody.
  • the chimeric antibody or fragment thereof according to the present disclosure can be prepared by using genetic recombination technology.
  • the chimeric antibody can be produced by cloning recombinant DNA comprising a promoter and a sequence encoding the variable region of the non-human and especially murine monoclonal antibody according to the present disclosure, and a sequence encoding the constant region of a human antibody.
  • the chimeric antibody of the present disclosure encoded by this recombinant gene will be, for example, a murine-human chimera, and the specificity of the antibody is determined by the variable region derived from murine DNA, and its isotype is determined by the constant region derived from human DNA.
  • Method for preparing chimeric antibodies can be found in, for example, Verhoeyn et al. (BioEssays, 8:74, 1988).
  • the term "monoclonal antibody” refers to a preparation of antibody molecules having a single molecular composition.
  • the monoclonal antibody composition shows a single binding specificity and affinity for a specific epitope.
  • AAJ8D6 antibody used herein, unless otherwise specified, refers to the humanized monoclonal antibody AAJ8D6 targeting c-Met obtained by the present inventors.
  • the cAAJ8D6 antibody used herein refers to a human-murine chimeric antibody comprising a murine variable region and a human constant region.
  • the difference between the cAAJ8D6 antibody and the AAJ8D6 antibody is only in the framework region in the variable region that the framework region of cAAJ8D6 is of murine origin, and the framework region of AAJ8D6 is of human origin.
  • the monoclonal antibody according to the present disclosure can be purified, for example, on an affinity column on which c-Met antigen has been immobilized in advance or which comprises one of the fragments of the epitope that can be specifically recognized by the monoclonal antibody according to the present disclosure. More specifically, the monoclonal antibody can be purified by protein A and/or G chromatography, in the presence or absence of ion exchange chromatography aimed at eliminating residual protein contaminants as well as DNA and LPS with or without size exclusion chromatography on Sepharose gels aimed at eliminating potential aggregates due to the presence of dimers or other multimers. More preferable, all of these techniques can be used simultaneously or sequentially.
  • Dolastatin refers to a polypeptide isolated from a marine organism, Dollabella auricularia, which includes, but is not limited to, dolastatin 10 and dolastatin 15. Dolastatin is a mitotic inhibitor that exhibits strong anticancer activity, and is therefore a candidate for anticancer drugs. The researchers further discovered and synthesized many derivatives of dolastatin, such as MMAE and MMAF.
  • linker or “linking group” as used herein refers to the moiety of an antibody-drug conjugate (i.e. ADC) that links an antibody to a drug, which may or may not be cleavable.
  • Cleavable linkers i.e., breakable linkers or biodegradable linkers
  • the linker of the present disclosure has very good stability, greatly reducing the release of the drug before delivery to the target (e.g., in the blood), thereby reducing side effects and toxicity.
  • the linker of the present disclosure is selected from cleavable linkers, such as disulfide-based linkers (which are selectively cleaved in tumor cells with higher thiol concentrations), peptide linkers (which are cleaved by enzymes in tumor cells) and hydrazone linker.
  • the linker of the present disclosure is selected from non-cleavable linkers, such as thioether linkers.
  • the linker of the present disclosure is selected from the group consisting of cleavable mc-vc-PAB linker and non-cleavable mc linker.
  • Heavy chain HCDR1 SEQ ID NO: 1 SYWMH HCDR2 SEQ ID NO: 2 MIDPSDSESRLNQKFKD HCDR3 SEQ ID NO: 3 SGYHGTSYWYFDV
  • Light chain LCDR1 SEQ ID NO: 4 RSSKSLLHSDGITYLY LCDR2 SEQ ID NO: 5 QMSNLAS LCDR3 SEQ ID NO: 6 AQNLELPPT
  • Amino acid sequence of the heavy chain variable region of anti-c-Met humanized antibody AAJ8D6 (SEQ ID NO: 7):
  • Amino acid sequence of the light chain variable region of anti-c-Met humanized antibody AAJ8D6 (SEQ ID NO: 8):
  • Amino acid sequence of the heavy chain of anti-c-Met humanized antibody AAJ8D6 (SEQ ID NO: 9):
  • Amino acid sequence of the light chain of anti-c-Met humanized antibody AAJ8D6 (SEQ ID NO: 10):
  • affinities of chimeric cAAJ8D6 and the humanized antibody AAJ8D6 were determined by ELISA.
  • a 96-well plate was coated with soluble ED protein and then incubated with diluted antibodies.
  • ED-related antibodies were detected with an HRP-conjugated goat F(ab')2 anti-human IgG Fc-specific secondary antibody.
  • the GraphPaD Prism software was used and X was changed to logX to fit a dose-response curve, which is shown in FIG. 1 .
  • the c-Met protein was prepared with a diluent to a final concentration of 2 ⁇ g/ml, and added to a microplate at 100 ⁇ l per well, overnight at 4°C. The solution in the well was discarded, and the plate was washed three times with PBST. The plate was added with a blocking solution at 300 ⁇ l/well and incubated at 37 °C for 2h. The solution in the well was discarded, and the plate was washed three times with PBST.
  • the preparation of antibody-drug conjugates was performed according to a general conjugation method: a reducing agent and a protecting agent were prepared with purified water as follows: 1-20 mM TCEP (Tris-2-carboxyethyl-phosphine) and 1-20 mM DTPA (Diethylene triamine pentacetate acid) mother liquor, where the amount of reducing agent can be added within a certain concentration range according to the required coupling rate, were mixed with a certain concentration of monoclonal antibody (such as: 5-30 mg/mL) according to a certain volume ratio (1:1), and the final concentration molar ratio of TCEP to antibody was 0.5-6.0:1.
  • the reaction was performed by stirring at 25°C for 1 h.
  • the TCEP-reduced antibody can be directly conjugated.
  • a certain concentration (5 mM) of a linker-active drug unit compound was prepared and dissolved in 25% DMSO (dimethyl sulfoxide). According to the molar ratio of drug to thio group of 0.3 ⁇ 2.8: 1, the drug was slowly added, and the reaction was performed by stirring at 25°C for 1-4 h. After the reaction, centrifugal ultrafiltration was performed 3 times with PBS buffer to purify and remove residual unreacted drugs and free small molecules such as DMSO, and SDS-PAGE electrophoresis and hydrophobic high performance liquid chromatography (HIC-HPLC) were used to detect the conjugation.
  • DMSO dimethyl sulfoxide
  • the linker-active drug unit compounds used in this example are Mc-Val-Cit-PAB-MMAE, D07-Val-Cit-PAB-MMAE and Py-MAA-Val-Cit-PAB-MMAE, whose structural formula are respectively as follows (for the synthesis methods, reference can be made to patent applications CN108853514A (page 14 of the specification), CN111433188A (page 53 of the specification), and WO2019223579A1 (pages 25-27 of the specification)). and
  • ADCs were prepared by the above method (p was an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8, q was an integer selected from 1, 2, 3 and 4, and Ab was the AAJ8D6 antibody provided by the present disclosure).
  • the average DAR of these ADCs was 4.
  • this example also prepared an antibody-drug conjugate whose antibody part was ABT-700 antibody, the linking group was Mc-Val-Cit-PAB, and the active drug unit was MMAE, where p is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8, and the average DAR was 4.
  • this example also prepared an antibody-drug conjugate of human immunoglobulin IgG1, Mc-Val-Cit-PAB and MMAE (i.e., IgG1-Mc-Val-Cit-PAB), where p was an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8, and the average DAR was 4.
  • HT29 cells were resuspended in 6-well plates at approximately 1 ⁇ 10 5 cells per well.
  • AAJ8D6 antibody, AAJ8D6-Mc-Val-Cit-MMAE, AAJ8D6-PY-Val-Cit-MMAE and AAJ8D6-D07-Val-Cit-MMAE were conjugated to pHAb amine-reactive dyes, respectively, and then diluted with cell culture medium to 10 ⁇ g/ml.
  • AAJ8D6 antibody 100 ⁇ l of AAJ8D6 antibody, AAJ8D6-Mc-Val-Cit-MMAE, AAJ8D6-PY-Val-Cit-MMAE and AAJ8D6-D07-Val-Cit-MMAE dye complexes were added to cells and incubated at 37°C for indicated times (0 h, 1 h, 3 h, 5 h, 21 h and 24 h).
  • the endocytosis effects of AAJ8D6 antibody, AAJ8D6-Mc-Val-Cit-MMAE, AAJ8D6-PY-Val-Cit-MMAE and AAJ8D6-D07-Val-Cit-MMAE were measured by flow cytometry.
  • Cells MKN-45, SNU-620, HT29, and BXPC-3 with different c-Met expression levels in exponential doubling phase were seeded in 96-well plates, respectively, and incubated overnight in a 37°C, 5% CO 2 incubator.
  • AAJ8D6, AAJ8D6-Mc-Val-Cit-MMAE and IgG1-Mc-Val-Cit-PAB were prepared in complete medium to a concentration of 1.25-2000 ng/mL, and MMAE was prepared in complete medium to a concentration of 0.0021-80 ng/mL. They were added to the plate at 100 ⁇ L per well with triplicate wells set up for each concentration, and a blank control group was set as well.
  • IR inhibition rate
  • Example 7 In vitro efficacy differences between antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE and antibody-drug conjugate ABT-700-Mc-Val-Cit-MMAE
  • the suspension of human colon cancer cell line HT29 was added to a 96-well plate at a density of 100 ⁇ L/well and 5000 cells/well, and placed in a water-saturated 37°C, CO 2 incubator overnight.
  • the antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE and the antibody-drug conjugate ABT-700-Mc-Val-Cit-MMAE were serially diluted and added to a 96-well plate containing cells at 100 ⁇ L/well. The plate was placed in a 37°C incubator to culture for another 72 h.
  • IR% (OD of blank-OD of drug) ⁇ 100/OD of blank.
  • the curve fitting software Softmax Pro7.0.3 Gxp was used to calculate IC 50 .
  • Example 8 Efficacy of antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE on human gastric cancer cell MKN-45subcutaneously transplanted tumors in Balb/c nude mice
  • mice were randomly divided into the Vehicle (PBS) group, IgG1-Mc-Val-Cit-PAB (3 mg/kg) group, antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE (0.75 mg/kg) group, antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE (1.5 mg/kg) group, antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE (3 mg/kg) and humanized antibody AAJ8D6 (3 mg/kg) group, 6 tumor-bearing mice in each group.
  • PBS Vehicle
  • IgG1-Mc-Val-Cit-PAB 3 mg/kg
  • antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE (0.75 mg/kg) group
  • antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE 1.5 mg/kg
  • TGI RTV tumor inhibition rate
  • TGI RTV (%) (1-T RTV /C RTV ) ⁇ 100%
  • T RTV means RTV of drug administration group or positive control group
  • C RTV means RTV of negative control group.
  • Table 6 Tumor volume and inhibition rate of each experimental group and control group on MKN-45 subcutaneously transplanted tumor in nude mice
  • TGI RTV % D0 D21 Vehicle (PBS) -- 201 ⁇ 25 1509 ⁇ 276 -- AAJ8D6 3 200 ⁇ 24 1633 ⁇ 77 -15
  • AAJ8D6-Mc-Val-Cit-MMAE 0.75 200 ⁇ 22 1135 ⁇ 74 22 1.5 203 ⁇ 23 415 ⁇ 50 70 3 201 ⁇ 22 36 ⁇ 9 99
  • the mouse PDX (patient-derived xenograft) model of gastric cancer GA0046 was constructed by transplanting tumor tissue from human patients with gastric cancer into severely immunodeficient mice, in which the gastric cancer tissue grew to form a transplanted tumor.
  • mice with good tumor growth were picked and euthanized, and the tumors were removed and cut into small pieces (2-3 mm in diameter), which were then inoculated on the right shoulder of the mice to establish a subcutaneous gastric cancer model.
  • the tumor growth was regularly observed, and when the tumor grew to an average volume of about 100-150 mm 3 , according to the tumor size and the weight of mice, mice were randomly divided into Vehicle (PBS) group, antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE (10 mg/kg) group, and IgG1-Mc-Val-Cit-PAB (10 mg/kg) group, 6 tumor-bearing mice in each group.
  • PBS Vehicle
  • AAJ8D6-Mc-Val-Cit-MMAE 10 mg/kg
  • IgG1-Mc-Val-Cit-PAB 10 mg/kg
  • TGI RTV tumor inhibition rate
  • TGI RTV (%) (1-T RTV /C RTV ) ⁇ 100%
  • T RTV means RTV of drug administration group or positive control group
  • C RTV means RTV of negative control group.
  • Table 7 Tumor volume and inhibition rate of antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE on mouse PDX model of gastric cancer GA0046 Group Tumor volume (mm 3 ) Inhibition rate (%) TV D0 TV D21 Vehicle(PBS) 133.90 ⁇ 18.34 1048.57 ⁇ 112.90 -- IgG1-Mc-Val-Cit-PAB 134.55 ⁇ 26.59 609.72 ⁇ 114.26 42.13 AAJ8D6-Mc-Val-Cit-MMAE 131.38 ⁇ 17.85 0.00 ⁇ 0.00 100.00
  • the mouse PDX (patient-derived xenograft) model of lung cancer LU2503 was constructed by transplanting tumor tissue from human patients with lung cancer into severely immunodeficient mice, in which the gastric cancer tissue grew to form a transplanted tumor.
  • mice with good tumor growth were picked and euthanized, and the tumors were removed and cut into small pieces (2-3 mm in diameter), which were then inoculated on the right shoulder of the mice to establish a subcutaneous lung cancer model.
  • the tumor growth was regularly observed, and when the tumor grew to an average volume of about 150 mm 3 , according to the tumor size and the body weight of mice, mice were randomly divided into Vehicle (PBS) group, humanized antibody AAJ8D6 (10 mg/kg) group, and low, medium and high concentrations of antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE (1.1 mg/kg, 3.3 mg/kg, 10 mg/kg) groups, 6 tumor-bearing mice in each group.
  • PBS Vehicle
  • AAJ8D6 humanized antibody AAJ8D6
  • AAJ8D6-Mc-Val-Cit-MMAE low, medium and high concentrations of antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE
  • mice in the antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE and humanized antibody AAJ8D6 groups were administered intravenously, once a week, for a total of 2 times.
  • the long diameter and short diameter of tumor and body weight were measured twice a week during the administration.
  • the tumor inhibition rate (TGI RTV ) was calculated for efficacy evaluation.
  • TGI RTV (%) (1-T RTV /C RTV ) ⁇ 100%
  • T RTV means RTV of drug administration group or positive control group
  • C RTV means RTV of negative control group.
  • mice The tumor inhibitory effects of each experimental group and control group on the mouse lung cancer PDX model (LU2503) are shown in Table 8 and FIG. 8 , in which Table 8 shows the tumor volume of and inhibition rate on the mouse lung cancer PDX model (LU2503), and FIG. 8 shows the tumor growth curve after administration.
  • Table 8 shows the tumor volume of and inhibition rate on the mouse lung cancer PDX model (LU2503)
  • FIG. 8 shows the tumor growth curve after administration.
  • the results showed that the antibody-drug conjugate AAJ8D6-Mc-Val-Cit-MMAE had a significant anti-tumor effect on the LU2503 tumor model when used alone at doses of 1.1 mg/kg, 3.3 mg/kg and 10 mg/kg, and especially at 3.3 mg/kg and 10 mg/kg, the tumors of mice completely disappeared.
  • Table 8 Tumor volume and inhibition rate of ADC on mouse PDX model (LU2503) Group Dose (mg/kg) Tumor volume (mm 3 ) Inhibition rate (%) TV D0 TV D21 Vehicle (PBS) -- 150.43 ⁇ 6.69 1864.30 ⁇ 228.19 -- AAJ8D6 10 157.05 ⁇ 9.21 1165.02 ⁇ 163.71 37.60 AAJ8D6-Mc-Val-Cit-MMAE 1.1 150.47 ⁇ 8.46 270.61 ⁇ 116.64 85.49 3.3 150.53 ⁇ 8.21 0.00 ⁇ 0.00 100.00 10 150.33 ⁇ 6.47 0.00 ⁇ 0.00 100.00
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